With a continuous increase in the world population and on-going aging tendency of the population, and due to extensive existence of various unhealthy life-styles including smoking as well as the environmental pollution, tumors have been the first killer threatening the human health in the developed countries, and the second killer threatening the human health in the developing countries (CA-Cancer. J. Clin. 2011, 61, 69-90). In China, cancers have been the first cause of death. The World Health Organization (WHO) has published “Global Cancer Report 2014” On Feb. 3, 2014, stating that the newly increased cancer cases and death cases are in the highest level in the world. Conventional chemotherapeutic drugs, such as alkylating agents, antimetabolites, etc., generally have disadvantages of high toxic and side effect and liability to drug resistance. Meanwhile, antitumor drugs designed against key proteins or kinases in signaling pathways are playing more and more important role in the field of tumor treatment. Therefore, it is greatly important to develop novel antitumor drugs with high efficacy and low toxicity, which is vital to the people's livelihood.
Proteasome is a macromolecular complex having multiple subunits and broadly distributed in eukaryotic cytoplasms and nuclei. The Proteasome has various catalytic functions, regulating metabolism of 80%-90% of proteins in the cell, and being involved in the cell cycle regulation, cell apoptosis, cell signaling, DNA repairing and various physiological functions, thereby playing important roles in the growth and development of cells. The proteasome plays regulatory roles in various life processes by regulating the level of key proteins (such as, P53, NF-κB) influencing the cell signaling pathway. Meanwhile, many of those regulatory proteins (such as, cyclins) play important role in oncogenesis and growth of tumors. The proteasome inhibitor may affect degradation of various cyclins in the cell and promote cell apoptosis by inhibiting activity of the proteasome.
In the past decades, small molecular compounds of various structures have been found to have proteasome inhibitory activity and strong antitumor effect. Currently, two small molecular proteasome inhibitors have been used clinically, namely, Bortezomib as a compound of peptide borates and Carfilzomib as a compound of epoxy ketone peptides. This further confirms validity of the proteasome as the target of tumor treatment.
In comparison with Bortezomib, Carfilzomib as an epoxy ketone compound not only has good tumor inhibitory effect, but also has no toxic and side effect of causing neurological injury shared by common proteasome inhibitors. The reason for this may be that Carfilzomib has more specific proteasome inhibitory activity and significantly lower inhibitory activity for other proteases as compared with Bortezomib (Clin Cancer Res. 2011, 17, 2734-2743). Carfilzomib developed by Onyx Pharmaceuticals, Inc. (U.S.A.) has been approved by the Food and Drug Administration (FDA) through an accelerated procedure in 2012, which is mainly used for treating the patient of multiple myeloma who has received at least two therapies of higher precedence (including Bortezomib, the first generation of proteasome inhibitor, and an immunomodulator). In comparison with the first generation of proteasome inhibitor, Carfilzomib is significant advantageous in that it may overcome the resistances to conventional antitumor drugs and have better safety, which render the treatment of multiple myeloma more hopeful.
Using Carfilzomib as a lead compound, the present disclosure has designed and synthesized a series of novel small molecular short peptide-based proteasome inhibitors, structurally featured in a tripeptide epoxy ketone compound constructed with a heterocycle. Such compounds have been evaluated for their proteasome inhibitory activity at molecular, cellular and animal levels. Meanwhile, they have been investigated for their antitumor activity at a cellular level and at an animal level. The results have shown that such compounds have an extremely strong proteasome inhibitory activity and cell proliferation inhibitory activity as a promising proteasome inhibitor, and may provide a new insight into the research of drugs for treating cancers.